6-Fluoro-5-nitroquinaldine

ABSTRACT

The compounds 8-bromo-6,7-dihydro-9-fluoro-5-methyl-1-oxo-1H,5H-benzo[ij]quiniolizine-2-carboxylic acid and 8-chloro-6,7-dihydro-9-fluoro-5-methyl-1-oxo-1H,5H,-benzo[ij]quinolizine-2-carboxylic acid are disclosed as potent antimicrobials. Pharmaceutically-acceptable carboxylate salts, acyl chlorides, esters and alkylaminoalkyl ester salts of the acids are also disclosed.

This is a division of application Ser. No. 318,927 filed Nov. 6, 1981,now U.S. Pat. No. 4,524,148.

TECHNICAL FIELD

This invention relates to derivatives of the heterocyclic system knownas benzo[ij]quinolizine. More specifically it relates to substituted6,7-dihydro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acidsand acyl chlorides, esters and salts thereof and the use of thesecompounds as antimicrobial agents. Intermediates for the preparation ofthe compounds and synthetic processes are also included within the scopeof the invention.

BACKGROUND ART

Certain substituted6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acids areknown to have antimicrobial activity and are disclosed in U.S. Pat. No.3,896,131 (Gerster). Gerster discloses compounds substituted by halogenin the 8 or 9 position, but no compound substituted by halogen in boththe 8 and 9 positions is described. It has now been found that certaincompounds substituted by two different halogens in the 8 and 9 positionsdemonstrate greatly enhanced antimicrobial activity against certain keyspecies of bacteria.

Specific compounds containing a halogen in the 8 or 9 position describedby Gerster in the aforementioned patent include the 9-fluoro compound,the 8-chloro compound, the 9-chloro compound, the 10-chloro compound andthe 9-bromo compound. Compounds substituted by halogen and oneadditional substituent in the 8 and 9 positions specifically disclosedby Gerster include: 8-chloro-9-methyl; 8-chloro-9-methoxy;8-amino-9-chloro; and 8-acetamido-9-chloro. Compounds of the presentinvention exhibit greatly improved antimicrobial activity over thehalogen-substituted compounds disclosed by Gerster.

DESCRIPTION OF THE INVENTION

This invention relates to the compounds8-bromo-6,7-dihydro-9-fluoro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylicacid;8-chloro-6,7-dihydro-9-fluoro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylicacid; and acyl chlorides, pharmaceutically-acceptable carboxylate salts,esters, and alkylaminoalkyl ester salts thereof.

The carboxylic acid compounds of the invention may be represented by thefollowing formula ##STR1## wherein X is bromo or chloro. In the acylhalide derivatives, the hydroxyl portion of the carboxylic acid group isremoved and replaced with a halide atom, preferably chlorine. In theester derivatives, the hydrogen portion of the carboxylic acid group isreplaced with an alkyl or substituted alkyl, preferably analkylaminoalkyl group.

Esters and acyl chlorides of the compounds of the invention may beobtained as intermediates during the preparation of the acidiccompounds, in some cases, or the esters may be prepared directly usingstandard synthetic methods. These esters and acyl chlorides exhibitantimicrobial activity, but they are primarily of interest as syntheticintermediates, although in some instances hydrolyzable or salt-formingesters may be of interest as therapeutic agents. Preferred esters arealkyl esters and alkylaminoalkyl esters having one to four carbon atomsin the alkyl group. Especially preferred are alkylaminoalkyl esters suchas the dimethylaminoethyl esters which will form salts, e.g.,hydrochlorides.

Ester derivatives are readily prepared by reacting the free acid ofFormula I with thionyl chloride to provide the novel acyl chloridederivative. The acyl chloride is reacted with the appropriate alcohol toprovide the desired ester.

It is well known to the art that pharmaceutically acceptable salts suchas alkali metal, alkaline earth, aluminum, iron and other metal andamine salts of pharmaceutically active acids are the equivalents of theacids, and in some cases may even offer advantages in absorption,formulation and the like. Pharmaceutically-acceptable carboxylate saltsof the free acid compounds of the invention are readily prepared byreaction of the acid with a base and evaporation to dryness. The basemay be organic, e.g., sodium methoxide or an amine, or inorganic, e.g.,sodium hydroxide. Alternatively, a carboxylate salt, e.g. the sodiumsalt, may be displaced by a second cation e.g. calcium or magnesium,when the salt of the second cation is more insoluble in a selectedsolvent such as water.

Compounds of the invention have an optically active carbon at the5-position. All such optical isomers are included within the scope ofthe invention.

The antimicrobial activity of the compounds of the present invention canbe demonstrated by the known, standard plate dilution method forbacterial susceptibility to antibiotics. The culture medium employedpermits susceptibility testing of fastidious microorganisms towardsantibiotics, sulfonamides and other chemotherapeutic agents. Tryptonesoy agar (oxoid) of the following composition is the culture medium.

    ______________________________________                                        Oxoid tryptone         15    g.                                               Oxoid soy peptone      5     g.                                               Sodium chloride        5     g.                                               Oxoid agar-agar No. 3  15    g.                                               Water                  1     liter                                            ______________________________________                                    

Using this test, the compounds of the invention have been found to havea broad spectrum of activity against gram-positive and gram-negativemicroorganisms.

The compounds of the invention are active against microorganisms eitherin the absence or presence of 10 percent horse serum.

The test procedure used to determine activity as employed in connectionwith the present invention provides information on the amount of acompound which gives complete inhibition, partial inhibition or noinhibition of microbial growth on the agar plates. In the tests, theselected compound is added to the agar medium to give concentrations ofzero, one, ten and one hundred milligrams per liter. A series of plateswith these concentrations is prepared. Ten percent horse serum is addedto one series of such plates. Aliquots of broth culture of any of twelvespecies of microorganisms are innoculated onto the agar plates contaningthe various compound concentrations. The plates are incubated at 37° C.in a 10 percent carbon dioxide atmosphere for 18 to 24 hours. Themicrobial growth on each plate is read visually, and minimal inhibitoryconcentrations are recorded. Some of the microorganisms which are usedfor this test are:

1. Staphylococcus aureus

2. Bacillus subtilus

3. Escherichia coli

4. Pseudomonas aeruginosa

5. Streptoccus sp.*

6. Asperigillus niger

7. Candida albicans

8. Acinetobacter lwoffi

9. Acinetobacter anitratum

10. Klebsiella pneumoniae

11. Streptococcus fecaelis

12. Serratia mercescens

All of the compounds of the invention (including salts, esters and acylhalides) possess antimicrobial activity towards one or more of the abovemicroorganisms. Of specific significance is their high level of activityagainst Pseudomonas aeruginosa, a particulary bothersome speciesassociated with many topical infections.

Each of the compounds of the invention have also shown activity againstone or more anaerobic bacteria, for example Bacteroides sp. andClostridium welchii. All of the acid compounds of the invention haveshown useful activity towards Erwinia amylovora, a gram-negativemicroorganism responsible for the plant disease known as fire blight.

It will be understood by those skilled in the art that the species usedare representative indicator species, as it would be impractical toscreen against all miroorganisms. It is well known in the art that broadspectrum activity can be predicted on the basis of activity shownagainst selected representative bacterial species of microorganisms.

All of the compounds of the invention are active when administeredorally to animals. They are excreted in the urine, and are effectiveurinary tract antibacterials in mammals. It is also contemplated thatthey may be used in the treatment of pulmonary infection, soft tissueinfection, burn infections and bacteremias.

All of the compounds of the invention are active against microorganismsin vitro or topically. In vitro activity is useful in itself, sinceantimicrobial agents may be used for disinfecting and sterilizing, e.g.,medical and dental equipment, as components of disinfecting solutions.

The acute oral toxicity of the compounds of the invention is generallymoderate to low compared with the effective oral dose, and they have anacceptable therapeutic ratio (LD₅₀ /ED₅₀).

The acidic compounds of the invention are ordinarily white or yellowishcrystalline or amorphous materials when purified. They are substantiallyinsoluble in water, lower alcohols or hydrocarbons and are more solublein halogenated solvents, N,N-dimethylformamide and the like. The estersare generally somewhat more soluble in organic solvents. The salts,especially the alkali metal salts, have appreciate solubility in waterand lower alcohols.

The compounds of the invention may be formulated by incorporating theminto conventional pharmaceutical vehicles, either organic or inorganic,which are suitable for oral or intraperitoneal application. For in vitroor topical use, simple aqueous solutions or suspensions are mostconveniently employed. For this purpose, concentrations of the order of100 parts per million up to about 5 parts per thousand are suitable, andthe formulation is used by immersing objects to be treated therein, orby local application to an infected area.

The amount of compound used to treat, for example, a microbial urinaryinfection by oral administration, will be an effective amount less thana toxic amount. The amount to be administered to control an infectionwill depend on the species, sex, weight, physical condition and manyother factors, but this judgment is well within the skill of the medicalart. Usually the amount will be less than 100 mg./kg. per dose.Conveniently this is administered in the form of conventionalpharmaceutical preparations such as capsules, tablets, emulsions,solutions and the like, Excipients, fillers, coatings, etc. aregenerally employed with tablets or capsules, as is well known in theart.

It is known to the art that antimicrobial agents are used as growthpromoters in various animal and bird species. Although not yet verified,it is inferred from the outstanding antimicrobial activity that thecompounds of the invention can be used for this purpose also. The acidcompounds of the invention may also be used for the control of microbial(e.g., Erwinia amylovora) infections of plants, e.g., by spraying ordusting formulations of these compounds on the affected area.

The compounds of the invention are prepared starting with the knowncompound 6-fluoroquinaldine.

6-Fluoroquinaldine is nitrated with fuming nitric and sulfuric acids inthe presence of sodium nitrite catalyst to provide the novel compound6-fluoro-5-nitroquinaldine.

The nitro group is reduced catalytically, for example in the presence ofpalladium on charcoal. If this reaction is carried out in the presenceof acetic anhydride the product is the novel compound5-acetamido-6-fluoroquinaldine. This intermediate is further reducedcatalytically in the presence of platinum on charcoal to provide thenovel compound 5-acetamido-6-fluorotetrahydroquinaldine.

The tetrahydroquinaldine intermediate is condensed with diethylethoxymethylenemalonate by heating without solvent at 100° to 200° C.(preferably 140° to 150° C. for two hours) for several hours. Theresulting novel intermediate is the compound of the formula: ##STR2##

This novel intermediate is an oil which need not be isolated orpurified. Instead, polyphosphoric acid is added, and the solution isheated at 100° to 140° C. to effect a condensation to provide an esterof the acids of Formula I wherein X is acetamido. The next step issaponification of the ester and hydrolysis of the acetamido group toprovide8-amino-6,7-dihydro-9-fluoro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylicacid, a novel intermediate. The 8-amino compound itself shows goodantimicrobial activity against many species of microorganisms. Thisintermediate is converted to the 8-chloro or 8-bromo derivative by theUllman modification of the Sandmeyer reaction in the presence ofhydrochloric or hydrobromic acid, respectively.

The following examples are provided to illustrate the synthetic methodsuseful to obtain compounds of the invention, and are not intended to belimiting of the invention.

EXAMPLE 1 Part A. Preparation of the novel intermediate6-Fluoro-5-nitroquinaldine

To 3.5 l of fuming sulfuric acid were added, with cooling, 600 g (3.73moles) of 6-fluoroquinaldine in small portions (5 to 10 g). To thismixture was added about 0.1 g of sodium nitrite, followed by thedropwise addition of 261 ml of fuming red nitric acid over a period ofsix hours. The temperature of the mixture was maintained at 5° to 10° C.during the addition. The mixture was stirred at 20° C. for sixteenhours, then poured into 3 gallons of ice. Ammonium hydroxide was added,with cooling, to basify the mixture. The precipitated solid wasseparated by filtration, and dissolved in about two liters of warmtoluene. The solution was dried over magnesium sulfate, filtered andevaporated to provide a yellow solid (6-fluoro-5-nitroquinaldine, m.p.105°-108° C.) which was recrystallized from 1,2dicholoroethane. Thestructural assignment was confirmed by nuclear magnetic resonance andinfrared spectral analyses.

Part B. Preparation of the novel intermediate5-Acetamido-6-fluoroquinaldine

To a mixture of 20 g (0.1 mole) of 6-fluoro-5-nitroquinaldine in 180 mlof ethyl acetate and 20 ml of acetic anhydride were added 3 g of tenpercent palladium on charcoal. The mixture was hydrogenated withhydrogen gas at 50 psi on a Paar apparatus for 20 minutes. Thetheoretical amount of hydrogen (25 psi) was used. On cooling, themixture solidified to a yellow mass. About 200 ml of ethanol was added,and the mixture was heated to dissolve the product. The catalyst wasfiltered off through celite, and the filtrate was evaporated to dryness,leaving a yellow solid. This solid was triturated with 200 ml of waterand neutralized with ten percent sodium hydroxide solution. Filtrationand drying provided white crystals of 5-acetamido-6-fluoroquinaldine,m.p. 232°-235° C. The structural assignment was confirmed by infraredspectral analysis.

Part C. Preparation of the novel intermediate5-Acetamido-6-fluorotetrahydroquinaldine

In one liter of acetic acid were dissolved 95 g of5-acetamido-6-fluoroquinaldine. To this mixture were added 10 g of fivepercent platinum on charcoal. The mixture was hydrogenated with hydrogengas at 30 psi on a Paar apparatus for five hours. The amount of hydrogenused was 61 psi (verus 62 psi theoretical). The catalyst was removed byfiltration, and the filtrate was concentrated to 250 ml and decantedinto cold stirred sodium hydroxide solution. The white precipitate wasseparated by filtration and triturated with a chloroform/hexane (50/50)mixture to provide white crystals of5-acetamido-6-fluorotetrahydroquinaldine, m.p. 168°-170° C. Thestructural assignment was confirmed by infrared spectral analysis.

Part D. Preparation of the novel intermediate Diethyl2-[N-(5-Acetamido-6-fluorotetrahydroquinaldinyl)]methylenemalonate

A stirred mixture of 6.4 g (28.8 mmole) of5-acetamido-6-fluorotetrahydroquinaldine and 8 g (37 mmole) of diethylethoxymethylenemalonate was heated at 140°-150° C. for two hours.Ethanol was allowed to evolve. The product, diethyl2-[N-(5-acetamido-6-fluorotetrahydroquinaldinyl)]methylenemalonate wasnot isolated.

Part E. Preparation of the novel intermediate8-Amino-6,7-dihydro-9-fluoro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylicAcid

The reaction mixture of part D containing diethyl2-[N-(5-acetamido-6-fluorotetrahydroquinaldinyl)]methylenemalonate wastreated with 25 g of polyphosphoric acid and warmed to 100° C. for 5minutes while stirring. Foaming was observed, demonstrating that thereaction had commenced. The external heating was removed and stirringwas continued for ten minutes. Heat was re-applied and the mixture wasmaintained at 100° C. for 0.5 hour. The cyclized product was thenhydrolyzed (ester portion) and deacetylated (acetamido group) by adding150 ml of water and 25 ml of methanol, basifying cautiously with fiftypercent sodium hydroxide solution and heating at reflux for 2.5 hours.Filtration through decolorizing charcoal and celite and decantation intorapidly stirring dilute acetic acid provided a tan solid, hydrated8-amino-6,7-dihydro-9-fluoro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylicacid, m.p. 300° C. Analysis: Calculated for C₁₄ H₁₃ FN₂ O.1/3H₂ O;%C,59.5; %H,4.8; %N, 9.9; Found: %C, 59.1; %H, 4.5; %N, 9.8

EXAMPLE 2

To 500 ml of 48 percent hydrobromic acid were added 14 g (50 mmole) of8-amino-6,7-dihydro-9-fluoro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylicacid. The mixture was cooled to 5° C. with an ice-salt bath. To thisstirred mixture 20 ml of 20 percent aqueous sodium nitrite solution wereadded dropwise over three minutes. Stirring was continued for tenminutes. To the solution were added 1.5 g of copper bronze. Stirring wascontinued for two hours at 20° C. The mixture was then heated on a steambath for 30 minutes. The mixture was decanted into 1.25 l. of water. Thetan solid was separated by filtration, then recrystallized from 200 mlof N,N-dimethylformamide. The product consisted of white crystals of8-bromo-6,7-dihydro-9-fluoro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylicacid, m.p. 282°-285° C. Analysis: Calculated for C₁₄ H₁₁ BrFNO₃ : %C,49.4; %H, 3.3; %N, 4.1; Found: %C, 49.8; %H, 3.0; %N, 4.3. Thestructural assignment was confirmed by infrared and nuclear magneticresonance spectral analyses.

EXAMPLE 3

A mixture of 15 ml of methanol and 15 ml of water containing 0.4 g (10mmole) of sodium hydroxide was heated on a steam bath to dissolve 2.3 g(6.7 mmoles) of8-bromo-6,7-dihydro-9-fluoro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylicacid. Cooling white stirring provided a cream-colored solid, hydratedsodium8-bromo-6,7-dihydro-9-fluoro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylate,m.p. 246° C. (dec.). Analysis: Calculated for C₁₄ H₁₀ BrFNNaO₃.1/3H₂ O:%C, 45.7; %H, 2.9; %N, 3.8; Found: %C, 45.7; %H, 2.9, %N, 3.8. Thestructural assignment was confirmed by infrared and nuclear magneticresonance spectral analyses.

EXAMPLE 4

In 100 ml of concentrated hydrochloric acid were dissolved 2.8 g (10mmole) of8-amino-6,7-dihydro-9-fluoro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylicacid. The mixture was cooled to 5° C. and 4 ml of 20 percent aqueoussodium nitrite solution was added dropwise with stirring. Stirring wascontinued at 5° C. for ten minutes. The ice bath was removed and 0.3 gof copper bronze was added. The mixture was stirred at 20° C. for twohours, then heated on a steam bath for ten minutes. The mixture wasdecanted into 250 ml of water. The tan solid precipitate was collectedby filtration, then recrystallized from 40 ml of N,N-dimethyformamide.The product was a light tan solid,8-chloro-6,7-dihydro-9-fluoro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylicacid, m.p. 288°-291° C. Analysis: Calculated for C₁₄ H₁₁ ClFNO₃ : %C,56.9; %H, 3.8; %N, 4.7; Found: %C, 57.0; %H, 3.7; %N, 4.7. Thestructural assignment was confirmed by infrared and nuclear magneticresonance spectral analyses.

EXAMPLE 5

To a mixture of 0.8 g (2.7 mmole) of8-chloro-6,7-dihydro-9-fluoro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylicacid and 20 ml of five percent sodium hydroxide solution were added 10ml of methanol. The mixture was heated to obtain a solution, then cooledwith stirring to provide a precipitate. The precipitate was washed withisopropanol, then with diethyl ether. The light tan solid was sodium8-chloro-6,7-dihydro-9-fluoro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylate,m.p. 250° C. (dec.). Analysis: Calculated for C₁₄ H₁₀ ClFNNaO₃ : %C,52.9; %H, 3.2; %N, 4.4; Found: %C, 52.4; %H, 3.0; %N, 4.3. Thestructural assignment was confirmed by infrared spectral analysis.

EXAMPLE 6

The antibacterial activity of the compounds of the present invention andtheir sodium salts was compared to that of compounds described byGerster in U.S. Pat. No. 3,896,131. Activity versus both gram negativeand gram positive bacteria was much higher for the compounds of thepresent invention than any of the prior art compounds. The tests wererun both in the absence and in the presence of horse serum as describedhereinabove. The results are shown in the table below:

    __________________________________________________________________________    Minimum Inhibitory Concentration (mg/l)                                                 STREP.                                                                              STAPHY.                                                                             ESCH.                                                                              PSEUDOMONAS        KLEBS.                          COMPOUND  SPECIES                                                                             AUREUS                                                                              COLI AERUGINOSA                                                                             ENTEROCOCCUS                                                                            PNEUMONIA                       __________________________________________________________________________    9-Cl      100                                                                              100                                                                              10  10                                                                               1                                                                               1  I   I   NA   NA   NA  NA                          9-F       100                                                                              100                                                                              10  10                                                                               1                                                                               1 100 100  100  100   1   1                          9-Br      100                                                                              100                                                                              100                                                                              100                                                                              10                                                                              10  I   I   NA   NA   NA  NA                          8-Cl, 9-CH.sub.3                                                                        100                                                                              100                                                                              10 100                                                                              10                                                                              10 100  I   100   I   100 100                         8-Cl       10                                                                              100                                                                               1  1  1                                                                               1 100 100   10   10   10  10                         8-Cl, 9-OCH.sub.3                                                                       100                                                                              100                                                                              10  10                                                                              10                                                                              10  I   I   100  100  100 100                         8-NH.sub.2, 9-Cl                                                                         I  I 100                                                                              100                                                                              10                                                                              10  I   I    I    I   100 100                         8-NHCOCH.sub.3, 9-Cl                                                                     I  I  I  I 10                                                                              10  I   I    I    I   100 100                         8-Br, 9-F  1  10                                                                               .1                                                                                .1                                                                              .1                                                                              .1                                                                               10 10    1    1    1   1                          8-Br, 9-F  1  10                                                                               .1                                                                                .1                                                                              .1                                                                              .1                                                                               10 10    1    1    1  1P                          sodium salt                                                                   8-Cl, 9-F 1P  10                                                                               .1                                                                              .1P                                                                               .1                                                                              .1                                                                               10 10    1    10   1   1                          8-Cl, 9-F 1P  10                                                                               .1                                                                              .1P                                                                               .1                                                                             .1P                                                                               10 10    1    1    1   1                          sodium salt                                                                   __________________________________________________________________________     I = Inactive                                                                  NA = Not Available                                                       

This test shows that the compounds of the invention are much better (upto 1000 times more active against some key species of bacteria)antibacterial agents than the compounds of the prior art. Against thebest compound of the prior art, the 9-Fl compound, compounds of thepresent invention are more active in 9 of 12 tests and at least equal inthe other 3 tests.

EXAMPLE 7

A mixture of 3.0 g of8-bromo-6,7-dihydro-9-fluoro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylicacid, 25 ml of thionyl chloride and 2 drops of N,N-dimethylformamide washeated on a steam bath for 15 minutes. The excess thionyl chloride wasremoved by evaporation. The residue of solid8-bromo-6,7-dihydro-9-fluoro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylchloride was suspended in 100 ml of dichloromethane, the mixture wasstirred and 10 ml of dimethylaminoethanol was added. After 10 minutes ofstirring the solution was washed with sodium bicarbonate solution, thendried over magnesium sulfate. The solution was treated with decolorizingcharcoal, filtered and concentrated to provide an oil. When cyclohexanewas added, tan solid N,N-dimethylaminoethyl8-bromo-6,7-dihydro-9-fluoro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylateformed. This product was dissolved in 50 ml of hot isopropanol, treatedwith decolorizing charcoal and filtered. A solution of isopropanolsaturated with hydrogen chloride gas was added until the mixture becameacidic. The white precipitate that formed was N,N-dimethylaminoethyl8-bromo-6,7-dihydro-9-fluoro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylatehydrochloride, m.p. 250° C. (dec.) Analysis: Calculated for C₁₈ H₂₀BrFN₂ O₃.HCl: %C, 48.3; %H, 4.7; %N, 6.2; Found: %C, 48.4; %H, 5.0; %N,6.2.

EXAMPLE 10

Solutions of 1.7 g sodium8-bromo-6,7-dihydro-9-fluoro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylatein 40 ml warm water and 2 g calcium chloride in 20 ml warm water werestirred together, heated on a steam bath for 15 minutes and cooled about16 hours. The product was separated by filtration, washed with water anddried to provide light pink calcium8-bromo-6,7-dihydro-9-fluoro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylatehydrate, m.p. >300° C. Analysis: Calculated for (C₁₄ H₁₀ BrFNO₃)₂Ca.1/2H₂ O: %C, 45.7; %H, 3.0; %N, 3.8; Found: %C, 45.7; %H, 3.2; %N,3.8. The structural assignment was confirmed by infrared spectralanalysis.

EXAMPLE 11

A solution of 1.0 g of sodium8-bromo-6,7-dihydro-9-fluoro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylatein 30 ml of warm water was stirred with 1 g magnesium sulfate in 20 mlof water and warmed on a steam bath for 15 minutes. Cooling andfiltration provided magnesium8-bromo-6,7-dihydro-9-fluoro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylatehydrate, m.p. >300° C. Analysis: Calculated for (C₁₄ H₁₀ BrFNO₃)₂ Mg.H₂O; %C, 47.1; %H, 3.0; %N, 3.9; Found: %C, 46.9; %H, 3.2; %N, 3.9.

What is claimed is:
 1. The compound 6-fluoro-5-nitroquinaldine.